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CORE II Block 2 > Lipid signaling > Flashcards

Lipid signaling Flashcards

1
Q

What components does lipid signaling involve?

A

Involves a lipid or lipid-derived molecule that binds to:

  • receptor (first messenger)
  • kinase/phosphatase (second messenger)
  • protein (second messenger)
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2
Q

Why are lipid signaling molecules transported with carrier protein if they can diffuse through the membrane?

A

It is much faster and more efficient. And, once inside the cell, the lipid signaling molecule (unless a polar derivative) will still be insoluble.

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3
Q

Why are lipid signaling molecules made on demand?

A

They are often not stored, so they are made only when needed and kept in the circulation on carrier proteins.

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4
Q

Where are phosphoinositides present in the cell?

A

inner leaflet of plasma membrane

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5
Q

what type of messenger are PIs?

A

second messenger

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6
Q

Describe structure of phosphoinositides

A

phospholipid - one saturated FA and one unsaturated. Inositol head group. often phosphorylated at C3 and C4 (PI(3,4)P2)

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7
Q

Describe metabolism of phosphoinositide by PLC.

A

Inositol head group can be phosphorylated on 4 or 5 in any order, but needs to have both phosphorylated in order for PLC to act on it to produce IP3 and DAG

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8
Q

Numbering of inositol head group.

A
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9
Q

How is PLC activated?

A

It is activated in a number of ways:

  1. by RTK to make PLCy
  2. by GPCR and alpha q G protein subunit to make PLC beta1
  3. by GPCR and G subunit beta gamma to make PLC beta2

The isoforms all do the same thing!!

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10
Q

Is IP3 a lipid?

A

No it is lipid derived, but is itself a soluble molecule

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11
Q

What is the dowstream effect of DAG?

A

it activates PKC

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12
Q

What is the downstream effect of IP3?

A

it releases Ca2+ from the ER

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13
Q

What is PLC alpha isoform?

A

It is not actually an isoform, but a proeolytic fragment from PLC delta

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14
Q

What PLC isoform is expressed by lower eukaryotes and prokaryotes?

A

PLC delta

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15
Q

What part of the PLC protein is made up by the X and Y domains?

A

the catalytic core

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16
Q

What is the pleckstrin homology domain in PLC?

A

PDH is a domain that facilitates binding to the plasma membrane via PIP3. The alpha helices bind onto the phospholipid.

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17
Q

Discuss the regenerative cycle of phosphoinositide resynthesis.

A

After PI4,5bisphosphate is cleaved by PLC to IP3 and DAG, the two second messengers are recycled in different ways:

IP3:

  • alkaline and acid phosphatases act on IP3 to create inositol
  • inositol acts with CDP-DAG to form phosphoinositide

DAG:

  • DAG removed from PI or made from cholesterol is coverted to phosphatidic acid
  • phosphatidic acid is converted to CDP-DAG, which acts with inositol to form PI
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18
Q

Why is phosphoinositide recycling kept to a minimum?

A

It is metabolically expensive

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19
Q

What is DGK? What is it involved in?

A

DGK = diacylglyerolkinase is the kinase which activates DAG with phosphate, making it phosphatidic acid

  • phosphorylation disrupts docking interactions of Ras, Rac, and PKC to DAG, downregulating the signals they transduce.
  • this downregulation is called T cell anergy which is the opposite of division in the immune response
  • is reversible. Phosphate just needs to be removed from phosphatidic acid
20
Q

What is PI3K? What is its effect on phosphoinositide?

A

It can act on any substrate to add phosphate to the third carbon of PI. PIP3 is still in the membrane and acts as a docking station for proteins with the pleckstrin homology domain.

21
Q

How is the PIP3 docking site disrupted?

A

PTEN dephosphorylated PIP3. PTEN is mutated in many tumors,

22
Q

What are the early steps of PIP3 inhibition of apoptosis?

A
  1. activatesd RTK
  2. RTK phosphorylats and activates PI3K
  3. PI3K phosphorylates PIP2 to make PIP3.
  4. PDK1 and Akt can dock to PIP3 because they have PHD
  5. Akt is activated and goes on to inhibit apoptosis
23
Q

Describe the role of PIP3 in scaffolding proteins.

A

PIP3 can help proteins with PHD hold onto docking stations to keep scaffolding between itself and RTK intact.

24
Q

Describe the PI3K structure.

A
  • p85 regulatory subunit
  • p110 catalytic subunit
  • 3 different classes with different subunit variations
25
Q

what is the antifungal antibiotic used to study PI3K?

A

wortmannin - inhibits p85

26
Q

List the functions phosphoinositides.

A
  1. to create DAG and IP3 second messengers
  2. docking sites for pleckstrin homology domains
  3. membrane trafficking
  4. maintenance of cytoskeleton
  5. regulation of ion channel activity
27
Q

How are fatty acids modified to play a role in lipid signaling?

A

fatty acid will be esterified to glycerol to generate arachidonic acid which makes the prostaglandin and leukotriene signaling molecules (first messenger..I think)

28
Q

Describe how prostaglandins and leukotrienes are made from arachidonic acid.

A
  • cyclo-oxygenases act on arachidonic acid to form prostaglandin H2. Different synthases act on prostaglandn H2 to make the other prostaglandins
  • lipo-oxygenases act on arachidonic acid to form HPETE which is then converted to leukotrienes
29
Q

What system are both prostaglandins and leukotrienes involved in?

A

inflammation

30
Q

Where did prostaglandins get their name? What are some examples of their functions?

A
  • first isolated from prostate gland secretions
  • constriction or dilation of vascular smooth muscle
  • aggregation and disaggregation of platelets
  • fever
31
Q

Where did leukotrienes get their name? What are some of their functions?

A
  • first isolaetd in leukotrienes
  • chemotactic for migrating neutrophils
  • increased vascular permeability
32
Q

Which arachidonic acid derivative is used to treat asthma?

A

leukotrienes

33
Q

Are prostaglandins first or second messengers? What receptors do they act on?

A

prostaglandins are first messengers and bind to GPCR.

34
Q

How are PPARs activated?

A

Fatty acid signaling molecules get into the cell by FABP (fatty acid binding proteins). FABP moves the signaling molecule into the nucleus, where the fatty acid moves to PPAR, which is then active and acts as a txn factor at PPAR-response elements

35
Q

Which system are sphingomyelin messengers involved in?

A

nervous system

36
Q

What are PPARs?

A

peroxisome proliferator-activated receptor. acts as txn factor

37
Q

How many isotypes of PPAR are there in mammals?

A

3

38
Q

What are the clinical implications of PPAR?

A
  • hyperlipidemia is treated using PPARalpha agonists called fibrates
  • type II diabetes is treated using PPARgamma ligand thiazolidinedione
39
Q

Which is the most important sphingomyelin-derived messenger?

A

ceremide

40
Q

List the functions of ceremide.

A
  1. apoptosis and senescence
  2. activates PP1 and PP2A phosphatases
  3. activates cathepsin D in lysosomes
  4. plays role in diabetes to inactivate AKT, decrease insulin responsiveness, and kills islets of langerhans
41
Q

What are the functions of sphingosine phosphate?

A
  • cell survival
  • cell mortility (binds to stress fibers and actin assembly to help with adhesion migration)
  • cell proliferation
  • inflammation
42
Q

How does spingosine phosphate facilitate txn?

A

On the promotor of the target gene, a complex of Sphingosine kinase, HDAC, and the repressor complex bind.

activation of PKC allows for phosphorylation and activatio of sphingosine kinase.

sphingosine kinase then phosphorylates and activates sphingosine

sphingosine phosphate acts to inhibit HDAC, so the acetyl remains on the promotor and the chromatin stays open

43
Q

What type of signaling molecule is sphingosine?

A

Sphingosine is not a signaling molecule. Sphingosine phosphate is. S1P in addition to directly affecting txn can be secreted from the cell and can activate GPCRs

44
Q

Where does sphingolipid metabolism begin?

A

In the ER

45
Q

Describe sphingolipid metabolism.

A
  • begins in ER where ceramide is made
  • ceramide is transported to golgi where it is converted to sphingomyelin
  • sphingomyelin is moved to the plasma membrane, where ceramide can be made
  • ceramide can be metabolized to sphingosine
  • sphingosine can be phosphorylated to sphingosine phosphate
46
Q

How are lipid mediators measured?

A
  1. extraction of organic from aqueous phase by dissolving material in chloroform, methanol, and water (sugars and inositol will end up in methanol and water phase, lipids will end up in chloroform phase)
  2. separation and quantification of phases using TLC, HPLC, or GC-MS
47
Q

Describe the metabolic pathway that allows for a protein to be anchored to the membrane.

A

farnesyl anchor is derived from the cholesterol pathway

  • mevalonate (cholesterol precursor) is converted to farnesyl pyrophosphate
  • farnesyl pyrophosphate is converted to farnesyl which anchors the protein via thioester linkage

CORE II Block 2 (6 decks)

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